Indinavir (Systemic)

Another commonly used name is
IDV{08}Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Antiviral (systemic)—

IndicationsGeneral considerations
Human immunodeficiency virus (HIV) isolates with reduced susceptibility to indinavir have been recovered from some patients treated with this medication {01}. Resistance correlated with the accumulation of mutations that resulted in the expression of amino acid substitutions at eleven residue positions in the viral protease {01}.

Cross-resistance between indinavir and reverse transcriptase inhibitors is thought to be unlikely because they affect different enzyme targets {01}. However, cross-resistance was observed between indinavir and ritonavir, another protease inhibitor {01}. Varying degrees of resistance have been noted between indinavir and other protease inhibitors {01}.Accepted

Human immunodeficiency virus (HIV) infection (treatment) or
Immunodeficiency syndrome, acquired (AIDS) (treatment)—Indinavir is indicated in combination with the nucleoside analogs or as monotherapy for the treatment of HIV infection or AIDS {01}.

Indinavir binds to the protease active site and inhibits the activity of human immunodeficiency virus (HIV) protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV {01}. This inhibition prevents cleavage of viral polyproteins and results in the formation of immature noninfectious viral particles {01}.Absorption:

Rapidly absorbed when taken on an empty stomach {01}. Administration of indinavir with a meal high in calories, fat, and protein resulted in an 84% reduction in peak plasma concentration (C max) and a 77% reduction in area under the plasma concentration–time curve (AUC) {01}. Administration with a lighter meal resulted in little or no change in C max or AUC {01}.Protein binding:

Hepatic; seven metabolites have been identified {01}. One is a glucuronide conjugate and six are oxidative metabolites; cytochrome P450 3A4 (CYP3A4) has been found to be the major enzyme responsible for formation of the oxidative metabolites {01}.Half-life:

Approximately 0.8 hour after administration in the fasted state {01}.Elimination:
Fecal—Approximately 83% of an administered radioactive dose was recovered in the feces. Radioactivity due to the parent medication in the feces was approximately 19% {01}.
Renal—Approximately 19% of an administered radioactive dose was recovered in the urine. Radioactivity due to the parent medication in the urine was approximately 9% {01}.
In dialysis—It is not known whether indinavir is dialyzable by peritoneal or hemodialysis {01}.

Precautions to ConsiderCarcinogenicity

In animal studies performed in mice, no increased incidence of any tumor type was observed. In rats, the highest dose tested was 640 mg/kg/day; at this dose a statistically significant increased incidence of thyroid adenomas was seen only in male rats. At that dose, daily systemic exposure in rats was approximately 1.3 times higher than daily systemic exposure in humans. {06}Mutagenicity

There has been no evidence of mutagenicity or genotoxicity in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage, in vitro and in vivo chromosomal aberration studies, and in vitro mammalian cell mutagenesis assays {01}.Pregnancy/Reproduction
Fertility—
There were no effects on mating, fertility, or embryo survival in female rats and no effects on mating performance seen in male rats at doses providing systemic exposure comparable to or slightly higher than that attained with the clinical dose. {01} Also, there were no effects observed on fertility or fecundity of untreated females mated with treated males. {01}

Pregnancy—An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to indinavir. Physicians are encouraged by the manufacturer to register patients by calling (800) 258-4263.{06}

Adequate and well-controlled studies have not been done in humans. {01} Hyperbilirubinemia has occurred during treatment with indinavir; it is unknown whether administration to the mother in the perinatal period will exacerbate physiologic hyperbilirubinemia in neonates. {01}

No evidence of teratogenicity was found in developmental toxicity studies performed in rats (at doses up to 640 mg/kg/day) , dogs (at doses up to 80 mg/kg/day), and rabbits (at doses up to 240 mg/kg/day) administered doses comparable to or slightly greater than those administered to humans. {01}{06} No treatment related external or visceral changes were observed in rats. In rats, there were treatment-related increases over controls in the incidence of supernumerary ribs at exposures at or below those in humans, and of cervical ribs at exposures comparable to or slightly greater than those in humans. {01} There were no external, visceral, or skeletal changes observed in rabbits or dogs. In all three species, there were no treatment-related effects on embryonic/fetal survival or fetal weights. {01}{06}

In rabbits, at a maternal dose of 240 mg/kg/day, no drug was detected in fetal plasma 1 hour after dosing. Fetal plasma drug levels 2 hours after dosing were approximately 3% of maternal plasma drug levels. In dogs, at a maternal dose of 80 mg/kg/day, fetal plasma drug levels were approximately 50% of maternal plasma drug level both 1 and 2 hours after dosing. In rats at maternal doses of 40 and 640 mg/kg/day, fetal plasma drug levels were approximately 10 to 15% and 10 to 20% of maternal plasma drug levels 1 to 2 hours after dosing, respectively. {06}

Indinavir was administered to Rhesus monkeys during the third trimester of pregnancy (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir caused an exacerbation of the transient hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately four fold above controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester of pregnancy. In Rhesus monkeys, fetal plasma drug levels were approximately 1 to 2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily. {06}

It is not known whether indinavir is distributed into human breast milk; {01} however, there exists the potential for adverse effects in nursing infants. {01} Nursing mothers are advised to discontinue breast-feeding if they are receiving indinavir. {01}

Indinavir is distributed into the milk of lactating rats. {01}Pediatrics

The optimal dosing regimen for the use of indinavir in pediatric patients has not been established. A dose of 500 mg/m2 every eight hours has been studied in uncontrolled studies of 70 children, 3 to 18 years of age. The pharmacokinetic profiles of indinavir at this dose were not comparable to profiles previously observed in adults receiving the recommended dose. Although viral suppression was observed in some of the 32 children who were followed on this regimen through 24 weeks, a substantially higher rate of nephrolithiasis was reported when compared to adult historical data. Physicians considering the use of indinavir in pediatric patients without other protease inhibitor options should be aware of the limited data available in this population and the increased risk of nephrolithiasis. {06}

Geriatrics

No information is available on the relationship of age to the effects of indinavir in geriatric patients.

Pharmacogenetics

The effects of gender were compared in 10 HIV seropositive women to HIV seropositive men, and differences in indinavir exposure, peak concentrations, and trough concentrations were seen. The percent change in the AUC and Cmax was shown to be a 13% decrease for females compared to males. The C8hhas shown a 22% decrease for females relative to males. The clinical significance of these differences is ot known. {06}

The effects of race seemed to be comparable in Caucasians and Blacks based on pharmacokinetic studies including 42 Caucasians (26 HIV positive) and 16 Blacks (4 HIV positive). {06}Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» P450 CYP3A4 substrates such as:» Cisapride or» Ergot derivatives or» Midazolam or» Pimozide or» Triazolam (Indinavir should not be administered concurrently with cisapride, ergot derivatives, midazolam, pimozide, and triazolam; because competition for CYP3A4 by indinavir could result in inhibition of the metabolism of these medications and elevated plasma concentrations, there is a potential for serious and/or life-threatening side effects;{01}{06})

Calcium Channel Blockers (calcium channel blockers are metabolized by CYP3A4 which is inhibited by indinavir; coadministration could result in increased plasma concentrations of calcium channel blockers and may increase or prolong therapeutic effect{06})

Cimetidine (concurrent administration does not affect the area under the plasma concentration-time curve [AUC] of indinavir {01})

Clarithromycin (concurrent use results in a 29% increase in the AUC of indinavir and a 53% increase in the AUC of clarithromycin; dosing modification is not required {01})

Contraceptives, estrogen-containing, oral (concurrent use of indinavir with an estrogen-containing oral contraceptive [Ortho-Novum 1/35®] results in a 24% increase in the AUC of ethinyl estradiol and a 26% increase in the AUC of norethindrone; dosing modification is not required {01})

CYP3A4 inducers, less potent, such as:
carbamazepine or
dexamethasone or
phenobarbital or
phenytoin (interactions have not been studied; should be used with caution because concurrent administration could result in decreased plasma concentrations of indinavir{06})

» Delavirdine (a dose reduction should be considered when administering delavirdine with indinavir due to an increase in indinavir plasma concentrations{06})

» Didanosine (if indinavir and didanosine are both part of a treatment regimen, they should be administered at least 1 hour apart on an empty stomach; a normal acidic pH may be necessary for the optimal absorption of indinavir, and didanosine requires a buffer to increase the pH so that acid does not rapidly degrade didanosine {01})

» Efavirenz (indinavir plasma concentrations, AUC and C max were decreased by approximately 31% and 16%, respectively, as a result of enzyme induction; a dose adjustment for indinavir is recommended when administering efavirenz concurrently{06})

Fluconazole (concurrent use results in a 19% decrease in the AUC of indinavir and no change in the AUC of fluconazole; dosing modification is not required {01})

Grapefruit juice (administration of a single 400-mg dose of indinavir with grapefruit juice results in a 26% decrease in the AUC of indinavir; dosing modification is not required {01})

» HMG-CoA inhibitors:» Lovastatin or» Simvastatin (concomitant use is not recommended, metabolized by the CYP3A4 pathway; increased risk of myopathy including rhabdomyolysis{06})

Isoniazid (concurrent administration results in a 13% increase in the AUC of isoniazid and no change in the AUC of indinavir; dosing modification is not required {01})

» Ketoconazole (concurrent use results in a 68% increase in the AUC of indinavir; a dosage reduction of indinavir is recommended when coadministered with ketoconazole {01})

Lamivudine or
Zidovudine (concurrent administration of zidovudine and indinavir results in a 13% increase in the AUC of indinavir and a 17% increase in the AUC of zidovudine; administration of indinavir with zidovudine and lamivudine results in no change in the AUC of indinavir, a 36% increase in AUC of zidovudine and a 6% decrease in AUC of lamivudine; dosing modification is not required {01})

Quinidine (administration of a single 400-mg dose of indinavir with 200 mg of quinidine sulfate results in a 10% decrease in the AUC of indinavir; dosing modification is not required {01})

» Rifabutin (concurrent use results in a 32% decrease in the AUC of indinavir and a 204% increase in the AUC of rifabutin; dosage reduction of rifabutin is recommended when indinavir is coadministered with rifabutin.{03}{04}{05} )

» Rifampin (because rifampin is a potent inducer of CYP3A4 concurrent use with indinavir is not recommended; coadministration resulted in 89% ± 9% decrease in indinavir AUC. {01}{06})

» St. John's Wort (Hypericum perforatum ) (concurrent use decreases the AUC0–8h of indinavir from 36 to 79% and decreases C8hfrom 49 to 99% may lead to loss of virological response and possible indinavir or protease inhibitor resistance{06}; concurrent use is not recommended)

Sulfamethoxazole and trimethoprim combination (concurrent administration results in no change in the AUC of indinavir and sulfamethoxazole, and a 19% increase in the AUC of trimethoprim; dosing modification is not required {01})

Stavudine (concurrent administration results in no change in the AUC of indinavir and a 25% increase in the AUC of stavudine; dosing modification is not required {01})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Bilirubin, total serum (asymptomatic hyperbilirubinemia [total bilirubin ³ 2.5 mg per dL], reported primarily as elevated indirect bilirubin, has occurred in approximately 10% of patients treated with indinavir; this was associated with elevations in ALT or AST in less than 1% of patients; it also occurred more frequently at doses > 2.4 grams per day {01})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:» Hypersensitivity to indinavir {01}Risk-benefit should be considered when the following medical problems exist
Hemophilia (spontaneous bleeding has been reported in patients with hemophilia types A and B who are being treated with protease inhibitors {01}; a causal relationship has not been established {01})

» Hepatitis (hepatitis cases resulting in hepatic failure and death has been reported in patients with confounding medical conditions and/or were receiving concomitant therapy; a causal relationship has not been established {06})

» Hepatic function impairment (it is recommended that the dosage of indinavir be lowered in patients with mild to moderate hepatic function impairment due to cirrhosis {01})

Hyperbilirubinemia (it is unknown if indinavir will exacerbate the physiologic hyperbilirubinemia seen in neonates; indirect hyperbilirubinemia has occurred frequently during indinavir treatment and has infrequently been associated with increases in serum transaminases {06})

Patient monitoringThe following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood glucose determinations (recommended to closely monitor patient's plasma glucose concentrations; development of hyperglycemia or diabetes may be associated with the use of protease inhibitors {02})

Side/Adverse Effects

Note: Nephrolithiasis/Urolithiasis (kidney stones) was reported in approximately 12.4% of adult patients and 29% in pediatric patients treated with indinavir. It was not usually associated with renal function impairment and resolved with hydration and temporary interruption of therapy. Nephrolithiasis/Urolithiasis was more likely to occur with increasing exposure to indinavir Acute hemolytic anemia, including cases resulting in death, have been reported in patients being treated with indinavir. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of indinavir.{06}{01}
The redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and “cushingoid appearance” have been reported in patients on protease inhibitor therapy. A causal relationship between these events and use of protease inhibitors has not been confirmed. {06}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Those indicating need for medical attentionIncidence more frequentKidney stones {01} (blood in urine; sharp back pain just below ribs)

Overdose
There are no reports of indinavir overdose in humans {01}. Single oral and intraperitoneal doses of indinavir up to 20 times the human dose in rats and 10 times the human dose in mice did not result in any deaths. {01}

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Indinavir (Systemic) .

Pregnancy—Hyperbilirubinemia has occurred during treatment with indinavir; it is unknown whether administration to the mother in the perinatal period will exacerbate physiologic hyperbilirubinemia in the neonate

Breast-feeding—Indinavir is distributed into the milk of lactating rats; it is not known if indinavir is distributed into human breast milk; therefore, breast-feeding should be discontinued
Other medications, especially, cisapride, didanosine, delavirdine, efavirenz, ergot derivatives, HMG-CoA inhibitors, itraconazole, ketoconazole, lovastatin midazolam, pimozide, rifabutin, rifampin, simvastatin, St. John's wort, sildenafil, , or triazolam
Other medical problems, especially hepatic function impairment and hepatitisProper use of this medication» Importance of taking indinavir with water 1 hour before or 2 hours after a meal; indinavir may also be taken with other liquids (skim milk, juice, coffee, or tea) or with a light meal (dry toast with jelly, juice, and coffee with skim milk and sugar, or corn flakes, skim milk and sugar)

» Importance of drinking at least 1.5 liters (approximately 48 ounces) of liquids over each 24-hour period

» Importance of not taking more medication than prescribed; importance of not discontinuing indinavir without checking with physician

» Compliance with full course of therapy

» Importance of not missing doses and of taking at evenly spaced times

Not sharing medication with others

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage; indinavir capsules are sensitive to moisture; indinavir should be stored and dispense in the original container and the desiccant should remain in the bottlePrecautions while using this medication» Because indinavir may interact with other medications, not taking any other medications (prescription or nonprescription) without first consulting your physician

General Dosing Information
The recommended dose of indinavir is 800 mg every eight hours, whether it is used alone or in combination with other antiretroviral agents {01}.

To help prevent kidney stones, it is recommended that patients drink at least 1.5 liters (approximately 48 ounces) of liquids over each 24-hour period {01}. Patients who experience kidney stones may require temporary interruption of therapy (e.g., 1 to 3 days) during the acute episode or discontinuation of therapy {01}.

Patients with mild to moderate hepatic function impairment due to cirrhosis require a dosage reduction to 600 mg every eight hours {01}.Diet/Nutrition
Administration of a single 400-mg dose of indinavir with grapefruit juice results in a 26% decrease in the area under the plasma concentration–time curve (AUC) of indinavir; dosing modification is not required {01}.

Oral Dosage FormsNote: The dosing and strengths of the dosage form available are expressed in terms of indinavir base (not the sulfate salt).

Indinavir should be dispensed and stored in the original container. The desiccant should remain in the original bottle.{06}Auxiliary labeling:
• Take on an empty stomach or with a light meal.{06}Drink plenty of fluids{06}
• Continue medicine for full time of treatment.
• Do not take other medications without physician's advice.